Traumatic Brain Injury (TBI) is the leading cause of death and disability among young adults in the US and worldwide. The pathophysiology of acute TBI is characterized by a cascade of primary and secondary cellular events set in motion by the initial injury, and ultimately leading to cerebral edema, cellular disruption and death. Tissue breakdown in TBI results in the release of structural proteins into the bloodstream, including S100B, GFAP, UCH-L1 and SBDP150. These proteins may serve as useful biomarkers of the severity of the injury and perhaps provide useful information about response to treatment. Preliminary data from our group suggest that serum levels of S100B, GFAP, UCH-L1 and SBDP150 are more accurate predictors of the extent of injury than the Glasgow Coma Scale and computed tomography. However, none of these potential biomarkers are sufficiently validated to assess their clinical utility. The studies proposed here will follow up and extend these initial studies with the goal of providing proof that one or more of these proteins is a useful diagnostic tool for assessing injury severity, guiding treatment decisions, and developing innovative TBI interventions. This proposal, Biomarkers of Injury and Outcome in ProTECT III (BIO-ProTECT), is designed to validate our preliminary findings by prospectively assessing biomarker levels in patients who are enrolled in the NIH sponsored double blind randomized, placebo-controlled multicenter Phase III clinical trial of intravenous progesterone in acute TBI entitled, Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment Trial (ProTECT III; D. Wright, PI). ProTECT III will randomize 1,140 patients at 17 centers in the US with the goal of determining if administration of progesterone is effective in improving outcome measured 6 months after injury. ProTECT III provides an ideal opportunity to a) validate the ability of promising biomarkers to predict outcome in TBI, b) demonstrate the utility of biomarkers as proxy indicators of the clinical effects of treatment with progesterone, and c) provide better definition of treatment outcome in ProTECT III by defining an optimal serum concentration of progesterone in the treatment of TBI. In our primary aim we will determine whether serum biomarkers of structural brain injury are independent predictors of clinical outcome assessed 6 months after moderate and severe TBI. We will develop a prognostic model to predict outcome and validate this predictive model using subjects enrolled in the ProTECT III trial. We will also assess whether biomarker levels measured 24 and 48 hours after randomization will be predictive of outcome at 6 months. In our secondary aim we will define the relationship between serum progesterone levels and treatment effect. We will evaluate whether steady state progesterone levels, measured 24 and 48 hours after randomization, correlate with a favorable outcome at 6 months. We will also explore whether diminished release of S100b, GFAP, UCH-L1 and SBDP150, measured at 24 and 48 hours, can serve as a readily identifiable surrogate measure of early treatment response to progesterone.